Accumulation of oxidative DMA damage in the human brain is implicated in the etiology of posttraumatic and age associated declines in brain function. In neurons, because of their high metabolic rate and prolonged life span, exposure to reactive oxygen species (ROS) is extensive and the risk for accumulation of nuclear and mitochondria! DMAdamage is amplified. Although recent studies demonstrate that neurons are equipped to repair nuclear and mitochondrial oxidative DMAdamage via the base excision repair (BER) pathway, the capacity for repair and the impact of repair on preservation of neurons are not well defined. With the support of this grant we have demonstrated that in a rat model of respiratory hypoxia, oxidative DMAdamage is formed and repaired in the brain. We have shown that expression levels and excision activities of BER enzymes vary in a brain region-specific manner and are differentially modulated by hypoxia. Our main objective is to identify mechanisms that determine the capacity for repair of oxidative DMA damage, and how the repair process is augmented in vivo, in the brain. The Central Hypothesis of this proposal is that neurons are equipped to repair oxidative DMAdamage via BER and that nuclear and mitochondrial BER is a component of a neuroprotective response, which varies in a brain region-specific manner. To test this hypothesis we have planned in vivo and in vitro studies with the following Specific Aims: 1) To characterize the transcriptional component in hypoxia-induced DMA repair in the rat brain. 2) To determine brain region-specific, hypoxia-induced changes in excision rates of mitochondrial and nuclear BER enzymes. 3) To identify functional consequences of post-translational modifications of BER enzymes in vitro and in vivo, in the brain. 4) To test in vitro the hypothesis that the base excision repair pathway is a component of the adaptive response to oxidative stress;modulation of BER enzymes in primary neurons. We expect that gaining a better understanding of molecular mechanisms underlying augmentation of DMA repair via the BER pathway will present an opportunity for novel drug development to protect the brain from adverse consequences of disrupted oxygen supply under pathologic conditions including, cerebral ischemia, stroke and trauma as well as in advance of invasive clinical procedures, which generate a heavy oxidative burden in the brain.